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International audience; The development of highly efficient enantioselective olefin metathesis catalysts is a significant challenge. Using optically pure chiral cyclic (alkyl)(amino)carbene (ChiCAAC) ligands combined with preliminary mechanistic insights and density functional theory (DFT) computations, we show that catalytic performances in this field can be impaired by the formation of rotamers before the enantio-determining step. Using DFT, we also demonstrate that these results can help accelerate the process of ligand discovery by providing faster methods to discriminate potential candidates.

Increasingly sophisticated programmable quantum simulators and quantum computers are opening unprecedented opportunities for exploring and exploiting the properties of highly entangled complex quantum systems. The complexity of large quantum systems is the source of their power, but also makes them difficult to control precisely or characterize accurately using measured classical data. We review recently developed protocols for probing the properties of complex many-qubit systems using measurement schemes that are practical using today's quantum platforms. In all these protocols, a quantum state is repeatedly prepared and measured in a randomly chosen basis; then a classical computer processes the measurement outcomes to estimate the desired property. The randomization of the measurement procedure has distinct advantages; for example, a single data set can be employed multiple times to pursue a variety of applications, and imperfections in the measurements are mapped to a simplified noise model that can more easily be mitigated. We discuss a range of use cases that have already been realized in quantum devices, including Hamiltonian simulation tasks, probes of quantum chaos, measurements of nonlocal order parameters, and comparison of quantum states produced in distantly separated laboratories. By providing a workable method for translating a complex quantum state into a succinct classical representation that preserves a rich variety of relevant physical properties, the randomized measurement toolbox strengthens our ability to grasp and control the quantum world.

What is this summary about? This is a summary of an article originally published in the journal Advances in Therapy. Cladribine tablets are approved for treating people with relapsing multiple sclerosis (shortened to MS). People with MS take cladribine tablets for 2 periods of 4 to 5 days per year. This analysis looks at the results from 2 studies called the CLARITY and CLARITY Extension studies. These studies looked at what effect a 2-year course of treatment with cladribine tablets had on disability over 5 years in people with MS. How was the analysis carried out? In this analysis, researchers measured disability worsening at regular intervals during the 2-year treatment period in the CLARITY study and thereafter in the 2-year CLARITY Extension study. As many patients had a bridging interval between CLARITY and CLARITY extension, the researchers were able to assess disability over a 5-year timeframe. What were the results? When measurements were taken at Year 5 of the study, disability remained stable in more than half of participants. Over the 5-year period, 70% of participants did not experience persistent disease worsening that lasted more than 6 months. What do the results mean? Researchers concluded that a 2-year course of cladribine tablets may provide long-term benefits on disability for up to 5 years. Clinical Trial Registration: NCT00213135 ( ClinicalTrials.gov ) Clinical Trial Registration: NCT00641537 ( ClinicalTrials.gov )

Multiple sclerosis (MS) is an unpredictable disease characterised by a highly variable disease onset and clinical course. Three main clinical phenotypes have been described. However, distinguishing between the two progressive forms of MS can be challenging for clinicians. This article examines how the diagnostic definitions of progressive MS impact clinical research, the design of clinical trials and, ultimately, treatment decisions.We carried out an extensive review of the literature highlighting differences in the definition of progressive forms of MS, and the importance of assessing the extent of the ongoing inflammatory component in MS when making treatment decisions.Inconsistent results in phase III clinical studies of treatments for progressive MS, may be attributable to differences in patient characteristics (e.g., age, clinical and radiological activity at baseline) and endpoint definitions. In both primary and secondary progressive MS, patients who are younger and have more active disease will derive the greatest benefit from the available treatments.We recommend making treatment decisions based on the individual patient's pattern of disease progression, as well as functional, clinical and imaging parameters, rather than on their clinical phenotype. Because the definition of progressive MS differs across clinical studies, careful selection of eligibility criteria and study endpoints is needed for future studies in patients with progressive MS.

To describe a cohort of pregnant women having suffered an out-of-hospital cardiac arrest (OHCA) and to compare them with nonpregnant women of childbearing age having suffered OHCA.Study data were extracted from the French National OHCA Registry between 2011 and 2021. We compared patients in terms of characteristics, care and survival.We included 3,645 women of childbearing age (15-44) who had suffered an OHCA; 55 of the women were pregnant. Pregnant women were younger than nonpregnant victims (30 vs. 35 years, p = 0.006) and were more likely to have a medical history (76.4% vs. 50.5%, p 0.001) and a medical cause of the OHCA (85.5% vs. 57.2%, p 0.001). Advanced Life Support was more frequently administered to pregnant women (98.2%, vs. 72.0%; p 0.001). In pregnant women, the median time of MICU arrival was 20 minutes for the Medical Intensive Care Unit with no difference with nonpregnant women. Survival rate on admission to hospital was higher among pregnant women (43.6% vs. 27.3%; p = 0.009). There was no difference in 30-day survival between pregnant and nonpregnant groups (14.5% vs. 7.3%; p = 0.061). Fetal survival was only observed for OHCAs that occurred during the pregnancy second or third trimester (survival rates: 10.0% and 23.5%, respectively).Our results show that resuscitation performance does not meet European Resuscitation Council's specific guidelines on OHCA in pregnant women. Although OHCA in pregnancy is rare, the associated prognosis is poor for both woman and fetus. Preventive measures should be reinforced, especially when pregnant women have medical history.

Background Surgical techniques for treatment of gynecomastia are increasingly less invasive. We described technical standardization of pediatric endoscopic subcutaneous mastectomy (PESMA) with liposuction. Methods All adolescents with primary gynecomastia, operated using PESMA with liposuction over the period June 2014–July 2021, were included. The video recording of procedures was analyzed to standardize the operative technique. After patient installation, 3 trocars were placed on the mid-axillary line. The technique included 5 steps: (1) subcutaneous injection of lipolysis solution and liposuction; (2) creation of working space using an inflated balloon; (3) gland dissection using 5-mm sealing device; (4) specimen extraction through the largest trocar orifice; and (5) placement of suction drainage tube. Results Twenty-four male adolescents, operated for Simon’s grade 2B and 3 gynecomastia using PESMA with liposuction over the study period, were included. Mean patient age was 16 years (range 15–18). Gynecomastia was bilateral in 19/24 (79.2%) and unilateral in 5/24 (20.8%). One (4.1%) conversion to open was reported. The mean operative time was 87 min (range 98–160) for unilateral and 160 min (range 140–250) for bilateral procedure. The mean length of stay was 2.2 days (range 1–4). Patients wore a thoracic belt for 15 up to 30 days postoperatively. Post-operative complications occurred in 5/24 (20.8%): 2- or 3 mm second-degree burns in 4 (16.7%) and subcutaneous seroma in 1 (4.1%). All complications were Clavien 2 grade and did not require further treatment. Aesthetic outcomes were very good in 21/24 (87.5%). Three (12.5%) boys had persistent minimal breast asymmetry but did never perceive it negatively. Conclusion PESMA combined with liposuction was feasible and safe for surgical treatment of gynecomastia in this selected cohort of patients. Although challenging, this procedure provided good aesthetic results, with no scars on the anterior thoracic wall. Standardization of the operative technique was a key point for successful outcome.

Background Siponimod is a sphingosine 1-phosphate receptor modulator approved for active secondary progressive multiple sclerosis (aSPMS) in most countries; however, phase 3 EXPAND study data are from an SPMS population with/without disease activity. A need exists to characterize efficacy/safety of siponimod in aSPMS. Methods Post hoc analysis of participants with aSPMS (≥ 1 relapse in 2 years before study and/or ≥ 1 T1 gadolinium-enhancing [Gd +] magnetic resonance imaging [MRI] lesions at baseline) receiving oral siponimod (2 mg/day) or placebo for up to 3 years in EXPAND. Endpoints: 3-month/6-month confirmed disability progression (3mCDP/6mCDP); 3-month confirmed ≥ 20% worsening in Timed 25-Foot Walk (T25FW); 6-month confirmed improvement/worsening in Symbol Digit Modalities Test (SDMT) scores (≥ 4-point change); T2 lesion volume (T2LV) change from baseline; number of T1 Gd + lesions baseline–month 24; number of new/enlarging (N/E) T2 lesions over all visits. Results Data from 779 participants with aSPMS were analysed. Siponimod reduced risk of 3mCDP/6mCDP vs placebo (by 31%/37%, respectively; p p = 0.007) and reduced risk of 6-month confirmed SDMT worsening (by 27%; p = 0.060). Siponimod was associated with less increase in T2LV (1316.3 vs 13.3 mm3; p p Conclusions In aSPMS, siponimod reduced risk of disability progression and was associated with benefits on cognition and MRI outcomes vs placebo. Trial registration ClinicalTrials.gov number: NCT01665144.

Background: Siponimod significantly reduced the risk of confirmed disability progression (CDP), worsening in cognitive processing speed (CPS), relapses, and magnetic resonance imaging (MRI) measures of brain atrophy and inflammation versus placebo in secondary progressive multiple sclerosis (SPMS) patients in the Phase 3 EXPAND study. Objective: The aim of this study was to assess long-term efficacy and safety of siponimod 2 mg/day from the EXPAND study including the extension part, up to > 5 years. Methods: In the open-label extension part, participants receiving placebo during the core part were switched to siponimod (placebo-siponimod group) and those on siponimod continued the same treatment (continuous siponimod group). Results: Continuous siponimod reduced the risk of 6-month CDP by 22% (hazard ratio (HR) (95% confidence interval (CI)): 0.78 (0.66–0.92) p = 0.0026) and 6-month confirmed worsening in CPS by 23% (HR (95% CI): 0.77 (0.65–0.92) p = 0.0047) versus the placebo-siponimod group. Sustained efficacy on annualized relapse rate, total and regional brain atrophy, and inflammatory disease activity was also observed. No new, unexpected safety signals for siponimod were identified over the long term. Conclusion: The sustained efficacy and consistent long-term safety profile of siponimod up to > 5 years support its clinical utility for long-term treatment of SPMS. Benefits in the continuous siponimod versus placebo-siponimod group highlight the significance of earlier treatment initiation. Trial registration number: NCT01665144

Study design Systematic review. Objectives To synthetise the available scientific literature reporting early interventions to prevent neurogenic lower urinary tract dysfunction (NLUTD) after acute supra-sacral spinal cord injury (SCI). Methods The present systematic review is reported according to the PRISMA guidelines and identified articles published through April 2021 in the PubMed, Embase, ScienceDirect and Scopus databases with terms for early interventions to prevent NLUTD after SCI. Abstract and full-text screenings were performed by three reviewers independently, while two reviewers performed data extraction independently. An article was considered relevant if it assessed: an in-vivo model of supra-sacral SCI, including a group undergoing an early intervention compared with at least one control group, and reporting clinical, urodynamic, biological and/or histological data. Results Of the 30 studies included in the final synthesis, 9 focused on neurotransmission, 2 on the inflammatory response, 10 on neurotrophicity, 9 on electrical nerve modulation and 1 on multi-system neuroprosthetic training. Overall, 29/30 studies reported significant improvement in urodynamic parameters, for both the storage and the voiding phase. These findings were often associated with substantial modifications at the bladder and spinal cord level, including up/downregulation of neurotransmitters and receptors expression, neural proliferation or axonal sprouting and a reduction of inflammatory response and apoptosis. Conclusions The present review supports the concept of early interventions to prevent NLUTD after supra-sacral SCI, allowing for the emergence of a potential preventive approach in the coming decades.

Background: Magnetic resonance imaging (MRI) measurements of gray matter (GM) atrophy and magnetization transfer ratio (MTR; correlate of myelination) may provide better insights than conventional MRI regarding brain tissue integrity/myelination in multiple sclerosis (MS). Objective: To examine the effect of siponimod in the EXPAND trial on whole-brain and GM atrophy, newly formed normalized magnetization transfer ratio (nMTR) lesions, and nMTR-assessed integrity of normal-appearing brain tissue (NABT), cortical GM (cGM), and normal-appearing white matter (NAWM). Methods: Patients with secondary progressive multiple sclerosis (SPMS) received siponimod (2 mg/day; n =1037) or placebo ( n = 523). Endpoints included percentage change from baseline to months 12/24 in whole-brain, cGM, and thalamic volumes; change in nMTR from baseline to months 12/24 in NABT, cGM, and NAWM; MTR recovery in newly formed lesions. Results: Compared with placebo, siponimod significantly reduced progression of whole-brain and GM atrophy over 12/24 months, and was associated with improvements in brain tissue integrity/myelination within newly formed nMTR lesions and across NABT, cGM, and NAWM over 24 months. Effects were consistent across age, disease duration, inflammatory activity subgroups, and disease severity. Conclusion: Siponimod reduced brain tissue damage in patients with SPMS as evidenced by objective measures of brain tissue integrity/myelination. This is consistent with central nervous system (CNS) effects observed in preclinical models. ClinicalTrials.gov number: NCT01665144.

Online ahead of print; International audience; Introduction: It is important to confirm the effectiveness and tolerability of disease-modifying treatments for relapsing-remitting multiple sclerosis (RRMS) in real-world treatment settings. This prospective observational cohort study (VIRGILE) was performed at the request of the French health authorities. The primary objective was to evaluate the effectiveness of fingolimod 0.5 mg in reducing the annualised relapse rate (ARR) in patients with RRMS.Methods: Participating neurologists enrolled all adult patients with RRMS starting fingolimod treatment between 2014 and 2016, who were followed for 3 years. Follow-up consultations took place at the investigator's discretion. The primary outcome measure was the change in ARR at month 24 after fingolimod initiation. Relapses and adverse events were documented at each consultation; disability assessment (EDSS) and magnetic resonance imagery were performed at the investigator's discretion.Results: Of 1055 eligible patients, 633 patients were assessable at month 36; 405 (64.0%) were treated continuously with fingolimod for 3 years. The ARR decreased from 0.92 ± 0.92 at inclusion to 0.31 ± 0.51 at month 24, a significant reduction of 0.58 [95% CI - 0.51 to - 0.65] relapses/year (p < 0.001). Since starting fingolimod, 461 patients (60.9%) remained relapse-free at month 24 and 366 patients (55.5%) at month 36. In multivariate analysis, no previous disease-modifying treatment, number of relapses in the previous year and lower EDSS score at inclusion were associated with a greater on-treatment reduction in ARR. The mean EDSS score remained stable over the course of the study. Sixty-one out of 289 (21.1%) patients presented new radiological signs of disease activity. Treatment-related serious adverse events were lymphopenia (N = 21), bradycardia (N = 19), elevated transaminases (N = 9) and macular oedema (N = 9).Conclusions: The effectiveness and tolerability of fingolimod in everyday clinical practice are consistent with findings of previous phase III studies. Our study highlights the utility of fingolimod for the long-term management of patients with multiple sclerosis.

Contains fulltext : 290866.pdf (Publisher’s version ) (Open Access) BACKGROUND: Management of focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA), is multidisciplinary and subject to practice variation. We aimed to evaluate variation in clinical management of FNH and HCA in Europe. METHODS: We distributed an online survey (November 2021-March 2022) among 294 European experts. The survey included questions on local practice and included eight clinical vignettes. The clinical vignettes focused on FNH or HCA management in the setting of sex, lifestyle modification, and pregnancy. RESULTS: The response rate was 32% and respondents included surgeons (38%), gastroenterologists/hepatologists (25%), radiologists (32%), and pathologists (1.6%) from ten European countries. We observed practice variation with regard to lifestyle modification and imaging follow-up in patients with FNH, and with regard to the management of HCA >5 cm before and during pregnancy. Finally, the management of HCA >5 cm after lifestyle modification deviated from EASL guideline recommendations. CONCLUSION: Our survey illustrates variability in FNH and HCA management in Europe. Several areas were identified for future research and guideline recommendations, including FNH follow-up and the management of HCA >5 cm. We propose the organization of Delphi consensus meetings to prioritize areas of research and update current guidelines to optimize management for all patients with benign liver tumors.

Supplemental material, sj-docx-6-dhj-10.1177_20552076231173531 for Development and usability testing of your MS questionnaire: A patient-based digital tool to monitor symptoms of multiple sclerosis by Gavin Giovannoni, Enrique Alvarez, Ellen Tutton, Olaf Hoffmann, Yan Xu, Patrick Vermersch, Celia Oreja-Guevara, Maria Trojano, Ralf Gold, René Robles-Cedeño, Mudeer Khwaja, Bianca Stadler, Jo Vandercappellen and Tjalf Ziemssen in DIGITAL HEALTH

Supplemental material, sj-docx-6-dhj-10.1177_20552076231173531 for Development and usability testing of your MS questionnaire: A patient-based digital tool to monitor symptoms of multiple sclerosis by Gavin Giovannoni, Enrique Alvarez, Ellen Tutton, Olaf Hoffmann, Yan Xu, Patrick Vermersch, Celia Oreja-Guevara, Maria Trojano, Ralf Gold, René Robles-Cedeño, Mudeer Khwaja, Bianca Stadler, Jo Vandercappellen and Tjalf Ziemssen in DIGITAL HEALTH

We present a technique for enhancing the estimation of quantum state properties by incorporating approximate prior knowledge about the quantum state of interest. This method involves performing randomized measurements on a quantum processor and comparing the results with those obtained from a classical computer that stores an approximation of the quantum state. We provide unbiased estimators for expectation values of multi-copy observables and present performance guarantees in terms of variance bounds which depend on the prior knowledge accuracy. We demonstrate the effectiveness of our approach through numerical experiments estimating polynomial approximations of the von Neumann entropy and quantum state fidelities.

Supplemental material, sj-docx-1-dhj-10.1177_20552076231173531 for Development and usability testing of your MS questionnaire: A patient-based digital tool to monitor symptoms of multiple sclerosis by Gavin Giovannoni, Enrique Alvarez, Ellen Tutton, Olaf Hoffmann, Yan Xu, Patrick Vermersch, Celia Oreja-Guevara, Maria Trojano, Ralf Gold, René Robles-Cedeño, Mudeer Khwaja, Bianca Stadler, Jo Vandercappellen and Tjalf Ziemssen in DIGITAL HEALTH

Supplemental material, sj-docx-2-dhj-10.1177_20552076231173531 for Development and usability testing of your MS questionnaire: A patient-based digital tool to monitor symptoms of multiple sclerosis by Gavin Giovannoni, Enrique Alvarez, Ellen Tutton, Olaf Hoffmann, Yan Xu, Patrick Vermersch, Celia Oreja-Guevara, Maria Trojano, Ralf Gold, René Robles-Cedeño, Mudeer Khwaja, Bianca Stadler, Jo Vandercappellen and Tjalf Ziemssen in DIGITAL HEALTH

Supplemental material, sj-docx-2-dhj-10.1177_20552076231173531 for Development and usability testing of your MS questionnaire: A patient-based digital tool to monitor symptoms of multiple sclerosis by Gavin Giovannoni, Enrique Alvarez, Ellen Tutton, Olaf Hoffmann, Yan Xu, Patrick Vermersch, Celia Oreja-Guevara, Maria Trojano, Ralf Gold, René Robles-Cedeño, Mudeer Khwaja, Bianca Stadler, Jo Vandercappellen and Tjalf Ziemssen in DIGITAL HEALTH

A simple experimental procedure for scaling carbene Bronsted basicity is described. The results highlight the strong basicity of pyrazol-4-ylidenes, a type of mesoionic carbene, also named cyclic-bentallenes (CBA). They are more basic (pKaH >42.7 in acetonitrile) than the popular proazaphosphatrane Verkade bases, and even the Schwesinger phosphazene superbase P4 (t Bu). The basicity of these compounds can readily be tuned, and they are accessible in multigram quantities. These results open new avenues for carbon centered superbases.

BACKGROUND Whole-body positron emission tomography/magnetic resonance imaging (WB-PET/MRI) is increasingly used in oncology. However, chest staging remains challenging. PURPOSE To compare the diagnostic performance of a free-breathing 3D-T1-GRE stack-of-stars volume interpolated breath-hold examination (StarVIBE) with that of a 3D-T1-GRE volume interpolated breath-hold examination (VIBE) during WB-PET/MRI for chest staging. STUDY TYPE Retrospective, cohort study. POPULATION One hundred and twenty-three patients were referred for initial staging of solid cancer, 46 of whom had pulmonary nodules and 14 had pulmonary metastasis. FIELD STRENGTH/SEQUENCE Free-breathing 3D-T1-GRE stack-of-stars (StarVIBE) and Cartesian 3D-T1-GRE VIBE at 3.0 T. ASSESSMENT Image quality was assessed using a 4-point scale and using the signal-to-noise ratio (SNR) of lung parenchyma and contrast-to-noise ratio (CNR) of pulmonary nodules. Diagnostic performances of both sequences were determined by three independent radiologists for detection of pulmonary nodules, lymph node involvement, and bone metastases using chest CT, pathology, and follow-up as reference standards. STATISTICAL TESTS Paired Student's t-test; chi-squared; Fisher's exact test. A P value

Les permanences d’accès aux soins de santé (PASS) ont été créées en 1998. L’objectif des PASS est de proposer aux personnes en situation de précarité une prise en charge médicosociale dans une perspective de retour vers le droit commun. Pour les patients en demande d’asile (DA) présents sur le territoire depuis moins de trois mois, les PASS constituent un lieu de soins préférentiel. En 2018, une instruction relative à la mise en place du parcours de santé des migrants primo-arrivants identifie les PASS comme une structure pivot pour les « rendez-vous santé » des primo-arrivants. Cette instruction, conjuguée aux recommandations concernant les actions d’« aller vers », a conduit à la construction à Marseille d’une action depuis 2020 : la PASS Mobile. Elle est constituée d’une équipe médicosociale et se déplace directement à la structure du premier accueil des demandeurs d’asile (SPADA). L’état actuel des connaissances concernant l’état de santé somatique et psychique des DA est pauvre. La PASS Mobile s’est donc engagée dans un projet de recherche dont l’objectif est de mesurer la prévalence de symptômes psychiatriques et des comorbidités somatiques chez les DA : PREMENTADA. Il s’agit d’une étude épidémiologique observationnelle transversale monocentrique de prévalence. Le critère de jugement principal est l’existence d’une symptomatologie anxieuse, dépressive ou de stress post-traumatique dépistée par un score du refugee health screener (RHS) 15 supérieur ou égal à 12 et/ou un score au thermomètre de détresse/d’angoisse supérieur ou égal à 5. La multimorbidité est évaluée par la « Cumulative illness rating scale » (CIRS), et la réalisation d’un prélèvement biologique permettra de mesurer la prévalence de certaines pathologies. PREMENTADA permettra de recueillir de premières données françaises concernant l’état de santé des DA primo-arrivants. Pour ces patients en DA venant d’arriver sur le territoire français, il revient aux référents des soins de premier recours de s’engager dans la construction de parcours de soins efficients : les médecins généralistes.

Background: No evidence of disease activity (NEDA-3) is a patient-centric outcome increasingly used as the goal of multiple sclerosis treatment. Objective: Determine treatment durability of cladribine tablets beyond 2 years considering the variable bridging interval of 0.1–116.0 weeks between CLARITY and CLARITY Extension. Methods: Between CLARITY and CLARITY Extension, patients transitioned from cladribine tablets 3.5 mg/kg to placebo (CP3.5 group, n = 98) or continued further treatment with cladribine tablets 3.5 mg/kg (CC7.0 group, n = 186). Treatment assignment was randomized and blinded in both CLARITY and CLARITY Extension. Results: The 2-year NEDA-3 in CLARITY Extension (encompassing both years of CLARITY Extension) was 29.6% in the CP3.5 group and 32.8% in the CC7.0 group. There was no evidence that treatment effect differed with varying bridging intervals. For patients in the CP3.5 group with a bridging interval of ⩽48 weeks, 1 year NEDA-3 (the first year of CLARITY Extension) was 44.4% (28/63) compared with 31.4% (11/35) in patients with a bridging interval of >48 weeks. Conclusion: Treatment with cladribine tablets in CLARITY, followed by either placebo or cladribine tablets in CLARITY Extension, produced sustained benefits for NEDA-3 and its constituent elements for a follow up period up to 6 years from CLARITY baseline.

Background Gait initiation is an automatized motor program that is preceded by anticipatory postural adjustments (APAs). During attentional tasks, these APAs can be modulated, producing multiple APAs. However, the role of the peripheral nervous system in the regulation of these APAs is unknown. Research question The objective of our study was to investigate whether APAs are also regulated by peripheral nervous afferents. Methods We assessed 21 patients suffering from chronic inflammatory demyelinating neuropathy and 20 healthy controls. Participants initiated gait with the right or left leg either freely (in the standard condition) or according to a visual trigger (i.e., the select condition). Kinetic and kinematic parameters of APAs and step initiation were recorded. Results The select condition was related to a higher rate of multiple APAs compared to the standard condition, and was more attention-consuming in both groups. The group with a neuropathy showed longer APAs than the control group, associated with a longer time to recover from multiple APAs. Consequently, the step execution time was delayed in patients with a peripheral neuropathy. Significance The impairment of the peripheral nervous system is therefore responsible for an alteration of the mechanisms underlying the recovery from multiple APAs during gait initiation. Our results are in favor of a role of proprioceptive afferents in the early peripheral regulation of motor errors. Further study on gait initiation in peripheral nervous disease could be helpful to better explore sensory-motor coupling in tasks requiring balance control.

The treatment strategy in relapsing multiple sclerosis (RMS) is a complex decision requiring individualization of treatment sequences to maximize clinical outcomes. Current local and international guidelines do not provide specific recommendation on the use of immune reconstitution therapy (IRT) as alternative to continuous immunosuppression in the management of RMS. The objective of the program was to provide consensus-based expert opinion on the optimal use of IRT in the management of RMS. A Delphi method was performed from May 2022 to July 2022. Nineteen clinical assertions were developed by a scientific committee and sent to 14 French clinical experts in MS alongside published literature. Two consecutive reproducible anonymous votes were conducted. Consensus on recommendations was achieved when more than 75% of the respondents agreed or disagreed with the clinical assertions. After the second round, consensus was achieved amongst 16 out of 19 propositions: 13 clinical assertions had a 100% consensus, 3 clinical assertions a consensus above 75% and 3 without consensus. Expert-agreed consensus is provided on topics related to the benefit of the early use of IRT from immunological and clinical perspectives, profiles of patients who may benefit most from the IRT strategy (e.g. patients with family planning, patient preference and lifestyle requirements). These French expert consensuses provide up-to-date relevant guidance on the use of IRT in clinical practice. The current program reflects status of knowledge in 2022 and should be updated in timely manner when further clinical data in IRT become available.

It has been over a year since people with multiple sclerosis (pwMS) have been receiving vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). With a negligible number of cases in which vaccination led to a relapse or new onset MS, experts around the world agree that the potential consequences of COVID-19 in pwMS by far outweigh the risks of vaccination. This article reviews the currently available types of anti-SARS-CoV-2 vaccines and the immune responses they elicit in pwMS treated with different DMTs. Findings to date highlight the importance of vaccine timing in relation to DMT dosing to maximize protection, and of encouraging pwMS to get booster doses when offered.

ImportanceWith few approved multiple sclerosis therapies in the pediatric population, there is a need for further approved treatment options. Limited data exist for dimethyl fumarate (DMF) treatment in pediatric-onset multiple sclerosis (POMS).ObjectiveTo compare the efficacy, safety, and tolerability of DMF vs intramuscular interferon β-1a (IFNβ-1a) in POMS.Design, Setting, and ParticipantsThe CONNECT study was an active-controlled, open-label, rater-blinded 96-week randomized clinical trial in patients with POMS aged 10 to less than 18 years treated between August 2014 and November 2020. Data were analyzed from January through October 2021.InterventionsPatients were randomized to DMF or IFNβ-1a.Main Outcomes and MeasuresThe primary end point was the proportion of patients free of new or newly enlarging (N or NE) T2 hyperintense lesions at week 96 among trial completers. Secondary end points included number of N or NE T2 lesions, proportion of patients free of relapse, annualized relapse rate (ARR), and safety. The estimated proportion of participants who were relapse free up to week 96 was calculated based on the Kaplan-Meier method. Adjusted ARR was obtained from a negative binomial regression adjusted for baseline relapse rate, baseline Expanded Disability Status Scale (EDSS) score, and age group.ResultsAmong 150 patients with POMS in the intention-to-treat (ITT) population (median [range] age, 15 [10-17] years; 101 [67.3%] female patients), 78 individuals received DMF and 72 individuals received IFNβ-1a. At week 96, the proportion of patients with no N or NE T2 hyperintense lesions among 103 trial completers was 16.1% (95% CI, 8.0%-27.7%) for DMF vs 4.9% (95% CI, 0.6%-16.5%) for IFNβ-1a, and in a sensitivity analysis among the ITT population, the proportions were 10 patients receiving DMF (12.8%) vs 2 patients receiving IFNβ-1a (2.8%). The estimated proportion of patients who remained relapse free at week 96 was 66.2% for DMF vs 52.3% for IFNβ-1a. Adjusted ARR (95% CI) at week 96 was 0.24 (95% CI, 0.15-0.39) for DMF vs 0.53 (95% CI, 0.33-0.84) for IFNβ-1a; the rate ratio for DMF vs IFNβ-1a was 0.46 (95% CI, 0.26-0.80; P = .006). The number of treatment-emergent adverse events (TEAEs; 74 patients [94.9%] vs 69 patients [95.8%]), serious TEAEs (18 patients [23.1%] vs 21 patients [29.2%]), and treatment discontinuations due to TEAEs (5 patients [6.4%] vs 8 patients [11.1%]) was similar for DMF vs IFNβ-1a.Conclusions and RelevanceThis study found that more pediatric patients with POMS treated with DMF were free of new or newly enlarging T2 lesions and that the adjusted ARR was lower among these patients compared with those treated with interferon β-1a. DMF was well tolerated.Trial RegistrationClinicalTrials.gov Identifier: NCT02283853

Context – Cybele asteroids constitute an appealing reservoir of primitive material genetically linked to the outer Solar system. The physical properties (size, shape) of the largest members can be directly measured with high-angular resolution imagers mounted on large (8-m class) telescopes. Aim – We took advantage of the bright apparition of the most iconic member of the Cybele population, (65) Cybele, in July and August 2021 to acquire high angular resolution images and optical light curves of the asteroid that were used to analyze its shape, topography and bulk properties (volume, density). Methods – Eight series of images were acquired with SPHERE+ZIMPOL on the Very Large Telescope (ESO Program ID 107.22QN.001; PI: Marsset) and combined with optical light curves to reconstruct the shape of the asteroid using the ADAM (Viikinkoski et al. 2015), MPCD (Capanna et al. 2013) and SAGE (Bartczak & Dudziński 2018) algorithms. Results – We will present Cybele’s bulk properties, including its volume-equivalent diameter and average density, in the context of other low-albedo P-type asteroids. We will show that Cybele’s shape and rotation state are entirely compatible to those of a Maclaurin equilibrium figure, opening up the possibility that D≥260 km (M≥1.4x10^19 kg) small bodies from the outer Solar System formed at equilibrium. We will further present the results of N-body simulations used to explore whether the equilibrium shape of Cybele is the result of a large resetting impact (similarly to the case of Hygiea; Vernazza et al. 2020), or if it is primordial (i.e., the result of early internal heating due to the radioactive decay of short- and long-lived radionuclides).

BackgroundMagnetic resonance imaging (MRI) measurements of gray matter (GM) atrophy and magnetization transfer ratio (MTR; correlate of myelination) may provide better insights than conventional MRI regarding brain tissue integrity/myelination in multiple sclerosis (MS).ObjectiveTo examine the effect of siponimod in the EXPAND trial on whole-brain and GM atrophy, newly formed normalized magnetization transfer ratio (nMTR) lesions, and nMTR-assessed integrity of normal-appearing brain tissue (NABT), cortical GM (cGM), and normal-appearing white matter (NAWM).MethodsPatients with secondary progressive multiple sclerosis (SPMS) received siponimod (2 mg/day; n =1037) or placebo (n = 523). Endpoints included percentage change from baseline to months 12/24 in whole-brain, cGM, and thalamic volumes; change in nMTR from baseline to months 12/24 in NABT, cGM, and NAWM; MTR recovery in newly formed lesions.ResultsCompared with placebo, siponimod significantly reduced progression of whole-brain and GM atrophy over 12/24 months, and was associated with improvements in brain tissue integrity/myelination within newly formed nMTR lesions and across NABT, cGM, and NAWM over 24 months. Effects were consistent across age, disease duration, inflammatory activity subgroups, and disease severity.ConclusionSiponimod reduced brain tissue damage in patients with SPMS as evidenced by objective measures of brain tissue integrity/myelination. This is consistent with central nervous system (CNS) effects observed in preclinical models. ClinicalTrials.gov number: NCT01665144.

Introduction In the Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) study, cladribine tablets significantly reduced relapse rates and improved findings on magnetic resonance imaging versus placebo in patients with relapsing multiple sclerosis. In the CLARITY Extension study, treatment with cladribine tablets for 2 years followed by placebo for 2 years produced similar clinical benefits to 4 years of cladribine tablets. The objective of this exploratory post hoc analysis was to evaluate long-term disease stability (assessed by the Expanded Disability Status Scale [EDSS] score) after treatment with cladribine tablets. Methods Patients enrolled into CLARITY Extension who were previously randomized to cladribine tablets 3.5 mg/kg in the CLARITY study were included in this post hoc analysis. Two treatment groups were investigated—patients randomized to cladribine tablets 3.5 mg/kg in CLARITY and thereafter randomized to placebo in CLARITY Extension (the CP3.5 group) or to cladribine tablets 3.5 mg/kg in CLARITY Extension (the CC7 group). In each treatment group, EDSS scores at 6-month intervals, EDSS score improvement/worsening each year, and time to 3- and 6-month confirmed EDSS progression were assessed from CLARITY baseline over 5 years of follow-up (including a variable bridging interval between studies). All analyses are descriptive, and no statistical comparisons were performed for between-treatment group differences. Results The median (95% confidence interval [CI]) EDSS score for patients in the CP3.5 group at 5 years was 2.5 (2.0–3.5) compared with 3.0 (2.5–3.5) at baseline. In the CC7 group, median EDSS score (95% CI) at 5 years was 2.0 (2.0–3.0) compared with 2.5 (2.5–3.0) at baseline. During year 5 for the CP3.5 group, and based on changes in minimum score each year, EDSS score stability was observed in 53.9% of patients, improvement in 21.3%, and worsening in 24.7%. In the CC7 group, EDSS score remained stable in 66.1%, improved in 18.1%, and worsened in 15.8% of patients. Over 70% of patients in both treatment groups did not show 3- or 6-month confirmed EDSS progression at 5 years from CLARITY baseline. Conclusions These findings confirm long-term beneficial effects on disability afforded by either the recommended dose of cladribine tablets over 4 years (cumulative dose, 3.5 mg/kg) or a higher cumulative dose. Trial Registration ClinicalTrials.gov NCT00213135 (CLARITY); NCT00641537 (CLARITY Extension).

Introduction In the 2-year CARE-MS trials (NCT00530348; NCT00548405) in patients with relapsing–remitting multiple sclerosis, alemtuzumab showed superior efficacy versus subcutaneous interferon beta-1a. Efficacy was maintained in two consecutive extensions (NCT00930553; NCT02255656). This post hoc analysis compared disability outcomes over 9 years among alemtuzumab-treated patients according to whether they experienced confirmed disability improvement (CDI) or worsening (CDW) or neither CDI nor CDW. Methods CARE-MS patients were randomized to receive two alemtuzumab courses (12 mg/day; 5 days at baseline; 3 days at 12 months), with additional as-needed 3-day courses in the extensions. CDI or CDW were defined as ≥ 1.0-point decrease or increase, respectively, in Expanded Disability Status Scale (EDSS) score from core study baseline confirmed over 6 months, assessed in patients with baseline EDSS score ≥ 2.0. Improved or stable EDSS scores were defined as ≥ 1-point decrease or ≤ 0.5-point change (either direction), respectively, from core study baseline. Functional systems (FS) scores were also assessed. Results Of 511 eligible patients, 43% experienced CDI and 34% experienced CDW at any time through year 9 (patients experiencing both CDI and CDW were counted in each individual group); 29% experienced neither CDI nor CDW. At year 9, patients with CDI had a −0.58-point mean EDSS score change from baseline; 88% had stable or improved EDSS scores. Improvements occurred across all FS, primarily in sensory, pyramidal, and cerebellar domains. Patients with CDW had a +1.71-point mean EDSS score change; 16% had stable or improved EDSS scores. Patients with neither CDI nor CDW had a −0.10-point mean EDSS score change; 98% had stable or improved EDSS scores. Conclusion CDI achievement at any point during the CARE-MS studies was associated with improved disability at year 9, highlighting the potential of alemtuzumab to change the multiple sclerosis course. Conversely, CDW at any point was associated with worsened disability at year 9. Supplementary Information The online version contains supplementary material available at 10.1007/s40120-021-00262-3.

Dealing with patients with both multiple sclerosis (MS) and inflammatory rheumatic disorders (IRDs) is not uncommon for a rheumatologist, as there is a statistical association between SpA and MS. As several CNS demyelinating events have been reported in patients treated with TNF inhibitor (TNFi), the pre-existing demyelinating disease was considered a contraindication for TNFi. However, this contraindication is mainly based on a randomized controlled trial in MS and not on large epidemiological studies. According to the last epidemiological studies, TNFi might not be an inducer of MS. Moreover, there are no clear recommendations on the use of the other DMARDs in patients suffering from an IRD and MS. In this review, we summarize the link between MS and IRDs and the impact of DMARDs on MS, especially TNFi. We also look at the impact of disease-modifying drugs for adults with MS and IRDs.

International audience; Background and purpose: Disease-modifying therapies (DMTs) have an impact on relapses and disease progression. Nonetheless, many patients with multiple sclerosis (MS) remain untreated. The objectives of the present study were to determine the proportion of untreated patients with MS followed in expert centers in France and to determine the predictive factors of nontreatment. Methods: We conducted a retrospective cohort study. Data were extracted from the 38 centers participating in the European Database for Multiple Sclerosis (EDMUS) on December 15, 2018, and patients with MS seen at least once during the study period (from June 15, 2016 to June 14, 2017) were included. Results: Of the 21,189 patients with MS (age 47.1 +/- 13.1 years; Expanded Disability Status Scale (EDSS) score 3.4 +/- 2.4), 6,631 (31.3%; 95% confidence interval [CI] 30.7-31.9) were not receiving any DMT. Although patients with a relapsing-remitting course (n = 11,693) were the most likely to receive DMT, 14.8% (95% CI 14.2-15.4) were still untreated (6.8% never treated). After multivariate analysis among patients with relapsing-remitting MS, the main factors explaining never having been treated were: not having >= 9 lesions on brain magnetic resonance imaging (odds ratio [OR] 0.52 [95% CI 0.44-0.61]) and lower EDSS score (OR 0.78 [95% CI 0.74-0.82]). Most patients with progressive MS (50.4% for secondary and 64.2% for primary progressive MS) did not receive any DMT during the study period, while 11.6% of patients with secondary and 34.0% of patients with primary progressive MS had never received any DMT. Conclusion: A significant proportion of patients with MS did not receive any DMT, even though such treatments are reimbursed by the healthcare system for French patients. This result highlights the unmet need for current DMTs for a large subgroup of patients with MS.